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Eholié et al. AIDS Res Ther (2016) 13:27
DOI 10.1186/s12981-016-0111-1
AIDS Research and Therapy
Open Access
REVIEW
Antiretroviral treatment regardless
of CD4 count: the universal answer
to a contextual question
Serge P. Eholié1,2,3*, Anani Badje2,3, Gérard M. Kouame3, Jean‑Baptiste N’takpe3, Raoul Moh1,2,3,
Christine Danel2,3 and Xavier Anglaret2,3
Abstract After a period where it was recommended to start antiretroviral therapy (ART) early, the CD4 threshold for treating
asymptomatic adults dropped to 200/mm3 at the beginning of the 2000s. This was mostly due to a great prudence
with regards to drug toxicity. The ART-start CD4 threshold in most international guidelines was then raised to 350/
mm3 in 2006–2009 and to 500/mm3 in 2009–2013. Between 2012 and 2015, international guidelines went the last
step further and recommended treating all HIV-infected adults regardless of their CD4 count. This ultimate step was
justified by the results of three randomized controlled trials, HPTN 052, Temprano ANRS 12136 and START. These three
trials assessed the benefits and risks of starting ART immediately upon inclusion (“early ART”) versus deferring ART
until the current starting criteria were met (“deferred ART”). Taken together, they recruited 8427 HIV-infected adults
in 37 countries. The primary outcome was severe morbidity, a composite outcome that included all-cause deaths,
AIDS diseases, and non-AIDS cancers in the three trials. The trial results were mutually consistent and reinforcing. The
overall risk of severe morbidity was significantly 44–57 % lower in patients randomized to early ART as compared to
deferred ART. Early ART also decreased the risk of AIDS, tuberculosis, invasive bacterial diseases and Kaposi’s sarcoma
considered separately. The incidence of severe morbidity was 3.2 and 3.5 times as high in HPTN052 and Temprano
as in START, respectively. This difference is mostly due to the geographical context of morbidity. The evidence is now
strong that initiating ART at high CD4 counts entails individual benefits worldwide, and that this is all the more true in
low resource contexts where tuberculosis and other bacterial diseases are highly prevalent. These benefits in addition
to population benefits consisting of preventing HIV transmission demonstrated in HPTN052, justify the recommenda‑
tion that HIV-infected persons should initiate ART regardless of CD4 count. This recommendation faces many chal‑
lenges, including the fact that switching from “treat at 500 CD4/mm3” to “treat everyone” not only requires more tests
and more drugs, but also more people to support patients and help them remain in care.
Keywords: Early antiretroviral treatment, Randomized controlled trial
Background
The optimal threshold for initiating ART: a 20‑year quest
1981–1996: The no‑treatment era
During the first 15 years of the HIV pandemic, no treatment could sustainably control the replication of the
virus and decrease mortality in HIV-infected people. The
*Correspondence: [email protected]
1
Service des Maladies Infectieuses et Tropicales, CHU de Treichville,
Abidjan, Côte d’Ivoire
Full list of author information is available at the end of the article
main direct and indirect consequence of the virus activity
was infected and uninfected CD4 + T cells (CD4) death,
causing progressively worsening immunosuppression,
which exposed patients to the growing risk of opportunistic infection and death. The degree of immunosuppression and the subsequent risk of death over time were
estimated with the CD4 count and with a clinical stage,
as determined based on the opportunistic diseases that
occurred in the patient. These two elements, CD4 count
and clinical stage, enabled the setting of thresholds for
some therapeutic decisions such as the initiation of
© 2016 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
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Eholié et al. AIDS Res Ther (2016) 13:27
prophylaxis for the major opportunistic infections. This
notion of “threshold” is crucial: it influenced the administration of anti-HIV treatments for almost 30 years.
1996: The sudden arrival of a highly potent treatment
In the mi-1990s, the arrival of combined antiretroviral
therapy (ART) revolutionizes the disease prognosis [1, 2].
This era is characterised by a combination of three factors: the evidence that combination therapy has a much
more potent and durable effect than monotherapy, the
introduction of protease inhibitors, and the capacity
to measure plasma viral load using the new molecular
amplification techniques. By controlling viral replication,
combination ART prevents cell death, increases CD4
count and restore immunity. This results in a dramatic
decline in the risk of opportunistic infection and death
[3]. In the first years of combination ART, “hit hard, hit
early” becomes the mantra, with the hope that exerting
maximal antiviral pressure on the virus during the initial phase of infection will prevent virus mutations and
favour treatment success [4].
Combination ART controls the virus, however, it does
not eradicate it. HIV reservoirs are shown to persist, even
if plasma viremia is successfully suppressed for prolonged
periods of time [5, 6]. From a fatal untreatable disease,
HIV infection thus becomes a chronic disease requiring lifelong treatment. Like any chronic therapy, ART
involves adherence issues and carries risks of cumulative
Page 2 of 9
toxicity; and like any anti-infective therapy, it carries risks
of emergence of resistance, especially if it is not taken
properly. To spare the patient unnecessary risks of toxicity and resistance, ART should therefore not be initiated
“too early”—i.e. at an immuno-clinical stage where the
treatment risks would outweigh the disease risks. This is
where the quest for the “optimal immuno-clinical threshold for initiating ART” begins.
1996–2014: Looking for the golden CD4 threshold
“When to start ART?” is essentially a risk/benefit question, but knowledge on benefits and risks changes over
time. During the first 10 years of ART, the ART-start
threshold fluctuates. After a short period in the late
1990s where it is recommended to start treatment from
500 CD4/mm3 without randomized trial evidence,
threshold for treating asymptomatic adults drops to 200/
mm3 at the beginning of the 2000s (Fig. 1) [7]. This shift
is mostly due to a great prudence with regards to drug
toxicity, especially cardiovascular or cerebrovascular,
metabolic and renal. This is the time when, in order to
spare toxicity, researchers carry out randomized trials of
structured treatment interruption (STI), in which ARTtreated patients whose CD4 count rises above 350/mm3
are proposed to temporarily interrupt their treatment [8,
9]. The underlying assumptions are that ART is the main
determinant of all the non-HIV adverse effects and illness being observed in the early era of combination ART,
Fig. 1 Temporal evolution of CD4 criteria to initiate ART in asymptomatic HIV+ adults (IAS, DHHS, EACS and WHO Guidelines)(1). (1) Adapted from
Marco Antonio Vitoria, WHO, Geneva. cART combined antiretroviral therapy. DHHS U.S. Department of Health and Human Services. EACS European
AIDS Clinical Society. IAS International AIDS Society. WHO World Health Organisation
Eholié et al. AIDS Res Ther (2016) 13:27
and that ART’s primary goal is to maintain CD4 above
200/mm3. Therefore, any drug exposure beyond this target potentially entails unnecessary side effects.
In 2006, the results of the STI trials annihilate this
approach. Contrary to the pre-trial hypotheses, the
Trivacan and SMART trials show that patients who temporarily interrupt ART at the threshold of 350 CD4/mm3
have higher risk of severe morbidity compared to those
who do not interrupt ART at the same threshold [8, 9].
In other words, below 350/mm3, HIV disease itself is
more toxic than antiretroviral drugs. Furthermore, STI
trial results no only suggest that people should worry
more about starting ART earlier than about interrupting
it. They shed important light on HIV morbidity, make us
focus back on the virus, and illustrate the importance of
the context.
In STI trials conducted in high resource countries, a
significant part of the extra morbidity related to treatment interruptions is made up of non-infectious diseases—non-AIDS cancers, cardiovascular and renal
diseases, and interruptions leads to a rise in inflammation markers [10, 11]. After more than 20 years of focusing on AIDS-defining opportunistic diseases (mostly
infectious) at low CD4 counts, the focus thus becomes on
non-AIDS HIV-related diseases (mostly non-infectious)
at high CD4 counts. Part of these diseases being likely
due to viral replication, rather than to immune suppression, the question is not whether the ART-start threshold
will continue to rise anymore, but how high it will get.
In STI trials conducted in low resource countries,
however, most of the extra morbidity related to treatment interruptions is made up of tuberculosis and invasive bacterial diseases [8, 12]. These infectious diseases
are more frequent in poor settings than in rich settings.
They are community diseases, but also act as opportunistic diseases, meaning that they are more frequent
in HIV-infected individuals than in HIV-non infected
ones. Thus, it is not that surprising that the overall risk
of severe morbidity in HIV-infected patients at any CD4
count is higher in low resource settings as compared to
high resource ones. Therefore, at the end of the 2000s,
if the case for raising the ART-start threshold is already
strong worldwide because of HIV non-AIDS non-infectious diseases, it is even stronger in regions where tuberculosis and bacterial diseases are more prevalent.
From there onwards the trend toward earlier initiation
of ART is unstoppable. Two multicohort studies from
industrialized countries suggest that 350/mm3 should
be the minimum threshold for initiation of antiretroviral
therapy [13, 14]. A randomized trial carried out in Haiti
demonstrates that starting ART immediately in patients
enrolled with less than 350 CD4/mm3 decreases the rates
of death and incident tuberculosis compared to starting
Page 3 of 9
ART at 200 CD4/mm3 [15]. Between 2006 and 2009 the
ART-start threshold is raised to 350/mm3 worldwide.
Between 2009 and 2013, most guidelines further set the
threshold to 500/mm3, the shift being quicker—with
some exceptions—in high resource countries than in low
resource ones. Raising the CD4 threshold to 500/mm3 is
based on high-quality evidence from HPTN052 that ART
reduces HIV transmission, but low-quality evidence from
cohort studies that ART reduces mortality or progression
to AIDS [16].
Finally, between 2012 and 2015, all international guidelines take the last step and recommend treating all HIVinfected adults regardless of their CD4 count [17–20].
This ultimate step is either corroborated or directly
inspired by the results of three randomized controlled
trials, HPTN 052, Temprano ANRS 12136 and START
[21–24].
HPTN 052, Temprano ANRS 12136 and START: the three
early ART trials
HPTN 052, Temprano and START were three open label
randomized controlled trials. They took place between
2007 and 2015. Taken together, they recruited a total
8427 HIV-infected adults in 37 countries, including 48 %
in Africa, 37 % in Europe, US, Australia or Israel, 17 % in
Latin America, and 10 % in Asia (Table 1; Fig. 2).
The three trials had the same primary objective, that is
to assess the benefits and risks of starting ART immediately upon inclusion (“early ART”) versus deferring ART
initiation until the current institutional starting criteria
were met (“deferred ART”). The primary outcome was
severe morbidity, a composite outcome that included allcause deaths, AIDS diseases, and non-AIDS cancers in
the three trials. In addition to these three components,
the primary outcome also included: severe bacterial diseases in Temprano and HPTN052; serious cardiovascular
diseases in START and HPTN052; diabetes mellitus in
HPTN052; and renal or liver failure in START. HPTN052
had a co-primary endpoint, HIV transmission to the
partner, and was primarily powered to interrogate HIV
transmission.
Asymptomatic patients were eligible for the trial if they
had CD4 counts between 350 and 550/mm3 in HPTN052,
between 250 and 800/mm3 in Temprano, and higher than
500/mm3 in START. As a consequence, the median CD4
count at baseline was 436/mm3 in HPTN052, 463/mm3
in Temprano and 651/mm3 in START, and the highest
CD4 count at baseline was 550/mm3 in HPTN052, 1456/
mm3 in Temprano and 2296/mm3 in START. In Temprano, 41 % of participants had more than 500 CD4/mm3
at baseline.
During the trial, asymptomatic patients randomized
into the deferred ART strategy started ART at 250/mm3
886
875
Early ART
Deferred ART
–
30 %
16 %
Europe, USA, Australia, Israel
Asia
Latin America
5 %
2.1 (1.5–2.9)
Follow-up, year, median (IQR)
ART-start CD4 threshold for asymptomatic patients randomized to the deferred ART strategy
2.5 (2.5–2.5)
2.8 (2.1–3.9)
NA
Myocardial infarction, stroke, or coronary revascularization
Temprano, patients were eligible for the trial if the pre-inclusion CD4 count (measured within 1 months prior to randomization) was below 800/mm3. The “baseline” CD4 count distribution shown here is the distribution
of values measured at inclusion (ie after informed consent), not the pre-inclusion value that determined eligibility. This explains why some patients had CD4 counts higher than 800/mm3 at baseline
e
d
Excluding HSV and oesophageal candidiasis
c
Asymptomatic participants assigned to the Deferred-ART strategy started ART: between the trial start and November 2009: whenever they met the WHO 2006 criteria for starting ART (CD4 count <200/mm3); Between
December 2009 and July 2013: whenever they met the WHO 2010 criteria for starting ART (CD4 count <350/mm3); Between August 1st 2013: whenever they met the WHO 2013 criteria for starting ART (CD4 count <500/
mm3; or stable partnership with an HIV-negative individual)
Asymptomatic patients were considered having ‘no WHO criteria for starting ART’ and therefore eligible for the trial: between the trial start and November 2009: if they had more than 250 CD4/mm3; Between December
2009 and July 2012: if they had more than 350 CD4/mm3; As enrolment was completed in July 2012, the WHO 2013 guidelines revision did not impact the eligibility criteria
Therefore, they adopted the WHO 2010 guidelines in December 2009 as soon as the WHO rapid advice was released; and further adopted the WHO 2013 guidelines in August 2013. The 2010 and 2013 guidelines revisions
impacted the trial procedures at two levels: the eligibility criterion ‘no WHO criteria for starting ART’, and the criteria for starting ART in participants assigned to the Deferred-ART strategy:
For ethical reasons, the Temprano investigators considered that the WHO revised guidelines had to be followed as soon as they were released
b
a
RCT randomized controlled trial; IPT isoniazid prophylaxis for tuberculosis
3 %
Received IPT during trial follow-up, %
Follow-up characteristics
45 %
9 %
436 (364–522; 550)
CD4 count, median (IQR; Max)
NA
463 (366–572; 1456e)
33 (27–39)
Positive serum HBs Ag
36 (29–44)
651 (584–765; 2296)
35 (29–42)
49 %
27 %
25 %
7 %
46 %
21 %
2359
2326
4588/4585
Age, median (IQR)
79 %
–
–
–
100 %
1023
1033
2076/2056
Death, AIDSc, non AIDS cancer, serious
cardiovasculard, renal failure, liver failure
350
% of women
Baseline characteristics
54 %
Africa
Geographical origin
1763/1761
Enrolled/analyzed
Number of participants
Death, WHO stage 4, non-AIDS cancers, tuberculosis, severe Death, AIDS, non AIDS cancers severe bacte‑
bacterial infections, serious cardiovascular, diabetes
rial infections
mellitus
Composite primary outcome
200–350–500b
250
ART initiation CD4 thresholda
Open label RCT
>500
250/350 < CD4 < 800b
350 < CD4 < 550
April 2009–May 2015
START
Open label RCT
Open label RCT
March 2008–Jan 2015
CD4 inclusion criterion
June 2007–May 2011
Temprano
Study design
Protocol
First enrolment–last visit
HPTN052
Table 1 Main characteristics of the three early ART randomized controlled trials (HPTN052, Temprano ANRS 12136, START)
Eholié et al. AIDS Res Ther (2016) 13:27
Page 4 of 9
Eholié et al. AIDS Res Ther (2016) 13:27
Page 5 of 9
Fig. 2 Geographical location of HPTN052, Temprano and START. Source Adapted from a Wikipedia map from http://www.vectorworldmap.com/;
public domain. Asterisks recruitment for the START trial in Europe: Germany 7 %, United Kingdom 7 %, Spain 5 %, Belgium 2 %, France 2 %, Greece
2 %, Denmark 1 %, Italy 1 %, Poland 1 %, Portugal 1 %, Switzerland 1 %, others (Czech republic, Estonia, Finland, Luxemburg, Norway, Sweden,
Ireland, all <1 %)
in HPTN052 and 350/mm3 in START. In Temprano,
the ART-start threshold was adjusted upward over time
according to WHO guidelines updates, from 200/mm3
in 2008–2009 to 350/mm3 in 2009–2013 and 500/mm3
in 2013–2015. The median follow-up in the trials varied
from 2.1 to 2.8 years.
Eholié et al. AIDS Res Ther (2016) 13:27
The three trials had notable differences in terms of
prevention and documentation of tuberculosis. Firstly,
Temprano was a factorial 2 × 2 trial assessing in parallel two questions: early ART, and early INH preventive
therapy (IPT). Therefore, participants were randomized
not only to early or deferred ART, but also to start or
not a 6-month course of IPT after 1 month of follow-up,
provided they had no signs or symptoms evocative of
tuberculosis. As a consequence, 45 % of participants in
Temprano received IPT, versus only 3 % in HPTN052 and
an unknown number in START. Secondly, in Temprano
and HPTN052 all cases of confirmed and probable tuberculosis were documented and included in the primary
outcome, while in START only confirmed cases with positive cultures were retained. The main results of the three
trials were mutually consistent and reinforcing in terms
of relative risks, while showing geographical context-specific absolute risks (Table 2).
In terms of absolute risks, the incidence of severe morbidity in the deferred ART strategy was 3.2 and 3.5 as
high in HPTN052 and Temprano compared to START,
respectively. This difference is likely explained by the context (more patients in low resource settings in HPTN052
and Temprano), the population (higher baseline CD4
count in SMART), and the differences in the documentation of tuberculosis discussed above.
In terms of relative risks, the overall risk of severe morbidity was 44–57 % lower in patients randomized to the
early ART strategy as compared to those randomized
to the deferred ART strategy in Temprano and START,
respectively. In Temprano, the reduction in severe morbidity was of similar magnitude and remained significant
when restricting the analysis to patients who had more
than 500 CD4/mm3 at baseline. In HPTN052, the overall
difference did not reach significance.
When considering separately each component of the
composite primary outcome or important secondary
outcomes, early ART significantly decreased the risk of:
AIDS in the three trials; tuberculosis considered separately in the three trials; invasive bacterial diseases in
Temprano and SMART; and Kaposi’s sarcoma in SMART.
These are secondary analysis whose power may be limited by the number of events in each group. As shown in
Table 2, the number of AIDS or non-AIDS HIV-related
events was lower with early ART than in deferred ART
in almost every subgroup, even if this difference did not
always reach significance. Of note, in Temprano, the trial
who assessed in parallel the efficacy of early ART and
IPT, IPT also reduced the risk tuberculosis by 66 % overall, 68 % in patients who had less than 500 CD4/mm3 at
baseline and 63 % in those who had more than 500 CD4/
mm3 at baseline. The efficacy of ART and IPT in reducing
tuberculosis was independent [22].
Page 6 of 9
Finally, in the three trials, ART appeared to be equally
well tolerated in both strategies (data not shown).
Discussion
These three trials were conducted in different geographical contexts and in populations at various immunosuppression stages. This diversity strengthens their common
conclusion: all over the world, HIV-infected persons
should be recommended to initiate ART regardless of
CD4 count. ART initiation should not be triggered by any
clinical or immunological threshold anymore, and the
objective of ART clearly becomes to suppress viral replication and prevent—rather than cure—inflammation and
immune deficiency.
Broadening treatment eligibility directly leads to
increase the number of individuals treated. Switching from treating at 500 CD4/mm3 to treating all HIVinfected persons irrespective of CD4 count meets many
barriers and challenges, especially in low resource settings. Of the 35 million people living with HIV, about 19
million do not even know that they are HIV-positive [25].
The majority of those who know their status still present
to care late with low CD4 counts [26]. We need a robust
testing agenda, including innovative approaches such
as community-based testing and self-testing to encourage early testing [27]. Furthermore, testing and initiating treatment early is not worth spending energy on it if
patients stop treatment afterwards. Therefore, initiating
ART irrespective of CD4 count in settings with high HIV
burden requires increased capacity not only in terms
of tests and drugs, but also in terms of infrastructures
and trained staff empowered to support patients [28].
In resource-constrained settings, a phased approach to
implementation may be needed [29, 30].
Finally, the randomized trials have shown that the
benefits/risk ratio of starting ART irrespective of CD4
count is favorable. However, if ART at any CD4 count
is proven to have strong benefits globally, the question
remains open of whether these benefits may outweigh
the risks in subgroups of patients, such as HIV controllers [31]. Therefore, now that we have given a global
answer to the question of ‘when to start ART’, we should
explore to question of ‘when not to start ART immediately’ at the individual level [16]. Should these challenges
be addressed, recommending initiating ART irrespective of CD4 count may bring benefits that extend beyond
the individual benefits demonstrated in HPTN 052,
Temprano and START. A person who starts treatment
earlier is less exposed to the initial complications of the
treatment such as immune constitution inflammatory
syndrome (IRIS), and thus easier to manage. In addition, not having to wait for a CD4 count result to decide
whether to initiate ART should facilitate and shorten
Eholié et al. AIDS Res Ther (2016) 13:27
Page 7 of 9
Table 2 Main outcomes of the three early ART randomized controlled trials (HPTN052, Temprano ANRS 12136, START)
Deferred ART
N
Early ART
Rate per 100 PY
N
Rate per 100 PY
Adjusted hazard
ratiof (95 % CI)
Composite primary outcome
HPTN052
91
4.5
71
3.5
0.73 (0.52–1.03)
Temprano
111
4.9
64
2.8
0.56 (0.41–0.76)
Baseline CD4 < 500
73
5.5
41
3.0
0.56 (0.38–0.83)
Baseline CD4 ≥ 500
38
4.1
23
2.4
0.56 (0.33–0.94)
96
1.4
42
0.6
0.43 (0.30–0.62)
START
Separated outcome
Deatha
HPTN052
15
NA
11
NA
0.73 (0.34–1.59)
Temprano
26
1.9
21
0.8
0.80 (0.45–1.40)
START
21
0.3
12
0.2
0.58 (0.28–1.17)
AIDSa
HPTN052
61
NA
40
NA
0.64 (0.43–0.96)
Temprano
65
2.8
33
1.4
0.50 (0.33–0.76)
START
50
0.7
14
0.2
0.28 (0.15–0.50)
Tuberculosisa,b
HPTN052
34
1.8
17
0.8
0.49 (0.28–0.89)
Temprano
55
2.4
28
1.2
0.50 (0.32–0.79)
START
20
0.3
6
0.1
0.29 (0.12–0.73)
AIDS and non-AIDS malignanciesa,c
HPTN052
7
NA
4
NA
NA
Temprano
6
NA
3
NA
NA
39
NA
14
NA
NA
START
Invasive bacterial diseasesd
HPTN052
13
NA
20
NA
NA
Temprano
36
1.5
14
0.6
0.39 (0.21–0.71)
START
36
0.5
14
0.2
0.38 (0.20–0.70)
Serious cardiovasculare
HPTN052
3
NA
1
NA
NA
Temprano
6
NA
3
NA
NA
14
0.20
12
0.17
0.84 (0.39–1.81)
START
N number of participants who had at least one such type of outcome; ART antiretroviral treatment; NA non available; PY person-years
a
Component of the composite primary outcome in the three trials
b
Total number of pulmonary and extra pulmonary TB episodes recorded in the three trials: HPTN052: pulmonary, n = 30 (early: 14; deferred: 16); extra-pulmonary,
n = 20 (early: 3; deferred: 17); Temprano ANRS 12136: pulmonary, n = 43 (early: 19; deferred: 24); extra-pulmonary, n = 41 (early: 9; deferred: 33). START: pulmonary,
n = 23 (early: 6; deferred: 17); extra-pulmonary, n = 3 (early: 0; deferred: 3)
c
Cervical carcinoma, Kaposi’s sarcoma, Lymphoma, Hodgkin’s, Lymphoma, non-Hodgkin’s non-AIDS cancers
d
Invasive bacterial diseases were a component of the composite primary outcome in Temprano and HPTN052, and a secondary outcome in START
e
Serious cardiovascular diseases were a component of the composite primary outcome in START and HPTN052, and a secondary outcome in Temprano
f
The trials analyses were adjusted for geographic regions (START) or study site (HPTN 052 and Temprano). In Temprano, Hazard Ratios were also adjusted for the IPT/
no IPT treatment
the pre-treatment period. These two advantages should
accelerate task delegation and help decentralize care,
thus increasing the likelihood that the UNAIDS target of
90 % of all people with diagnosed HIV infection receiving sustained ART will be reached by 2020 [32] . In addition, ART does not just reduce morbidity in the treated
individuals, it also reduces the number of people with a
detectable viral load. It thus contributes to reducing HIV
transmission and to controlling the HIV epidemic [24].
Finally, in the many countries where HIV and tuberculosis are both highly prevalent, ART and IPT independently decrease the risk of tuberculosis in HIV-infected
patients, even at high CD4 counts. Therefore, initiating
ART early should help decrease the risk of tuberculosis
Eholié et al. AIDS Res Ther (2016) 13:27
transmission and further contribute to tuberculosis control [33] and IPT should be given even to patients who
start ART at high CD4 counts [22].
Conclusions
In conclusion, the evidence is now strong that initiating ART at high CD4 counts entails individual benefits,
and that this is all the more true for those who live in low
resource contexts. These individual benefits in addition
to previously demonstrated population benefits, consisting of preventing HIV transmission to non-HIV-infected
partners, fully justify the universal recommendation that
HIV-infected persons should be recommended to initiate ART regardless of CD4 count. This recommendation
faces many challenges, including the fact that switching from “treat at 500 CD4/mm3” to “treat everyone” is
not only a matter of more tests and more drugs. It also
requires more people to support patients and help them
remain in care once they started treatment. Over the past
years, the “Test and Treat” model has evolved to “Seek,
Test, Treat and Retain”. Until HIV can be eradicated, it
should now be formulated this way: “Seek, test and treat
every HIV infected persons, and empower staff and
patients to ensure lifelong treatment continuity” [28].
Authors’ contributions
All authors helped to draft the manuscript. All authors read and approved the
final manuscript.
Author details
1
Service des Maladies Infectieuses et Tropicales, CHU de Treichville, Abidjan,
Côte d’Ivoire. 2 Inserm U1219, Université de Bordeaux, Bordeaux, France. 3 Pro‑
gramme PACCI-ANRS Research Site, Abidjan, Côte d’Ivoire.
Acknowledgements
Funding support:
Thanks to the French National Agency for AIDS and viral hepatitis research
(ANRS, Paris, France; Grants ANRS 12136, ANRS 12224, ANRS 12253): Brigitte
Bazin, Jean François Delfraissy (director), Pauline Justumus, Thierry Menvielle,
Aurélien Mollard, Claire Rekacewicz, Marie de Solere.
Competing interests
The authors declare that they have no competing interests.
Received: 9 April 2016 Accepted: 12 July 2016
References
1. Hammer SM, Squires KE, Hughes MD, Grimes JM, Demeter LM, Currier
JS, et al. A controlled trial of two nucleoside analogues plus indinavir
in persons with human immunodeficiency virus infection and CD4 cell
counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320
Study Team. N Engl J Med. 1997;337(11):725–33.
2. Gulick RM, Mellors JW, Havlir D, Eron JJ, Gonzalez C, McMahon D, et al.
Treatment with indinavir, zidovudine, and lamivudine in adults with
human immunodeficiency virus infection and prior antiretroviral therapy.
N Engl J Med. 1997;337(11):734–9.
3. Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA,
et al. Declining morbidity and mortality among patients with advanced
human immunodeficiency virus infection. HIV Outpatient Study Investi‑
gators. N Engl J Med. 1998;338(13):853–60.
Page 8 of 9
4. Ho DD. Time to hit HIV, early and hard. N Engl J Med. 1995;333(7):450–1.
5. Chun TW, Stuyver L, Mizell SB, Ehler LA, Mican JA, Baseler M, et al. Pres‑
ence of an inducible HIV-1 latent reservoir during highly active antiretro‑
viral therapy. Proc Natl Acad Sci U S A. 1997;94(24):13193–7.
6. Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, Chaisson RE, et al.
Identification of a reservoir for HIV-1 in patients on highly active antiretro‑
viral therapy. Science. 1997;278(5341):1295–300.
7. Yeni PG, Hammer SM, Carpenter CC, Cooper DA, Fischl MA, Gatell JM,
et al. Antiretroviral treatment for adult HIV infection in 2002: updated
recommendations of the International AIDS Society-USA Panel. JAMA.
2002;288(2):222–35.
8. Danel C, Moh R, Minga A, Anzian A, Ba-Gomis O, Kanga C, et al. CD4guided structured antiretroviral treatment interruption strategy in HIVinfected adults in west Africa (Trivacan ANRS 1269 trial): a randomised
trial. Lancet. 2006;367(9527):1981–9.
9. El-Sadr WM, Lundgren J, Neaton JD, Gordin F, Abrams D, Arduino RC, et al.
CD4+ count-guided interruption of antiretroviral treatment. N Engl J
Med. 2006;355(22):2283–96.
10. Emery S, Neuhaus JA, Phillips AN, Babiker A, Cohen CJ, Gatell JM, et al.
Major clinical outcomes in antiretroviral therapy (ART)-naive participants
and in those not receiving ART at baseline in the SMART study. J Infect
Dis. 2008;197(8):1133–44.
11. Rodger AJ, Fox Z, Lundgren JD, Kuller LH, Boesecke C, Gey D, et al. Activa‑
tion and coagulation biomarkers are independent predictors of the
development of opportunistic disease in patients with HIV infection. J
Infect Dis. 2009;200(6):973–83.
12. Dart Trial Team. Fixed duration interruptions are inferior to continuous
treatment in African adults starting therapy with CD4 cell counts <200
cells/microl. AIDS. 2008;22(2):237–47.
13. Kitahata MM, Gange SJ, Abraham AG, Merriman B, Saag MS, Justice
AC, et al. Effect of early versus deferred antiretroviral therapy for HIV on
survival. N Engl J Med. 2009;360(18):1815–26.
14. Sterne JA, May M, Costagliola D, de Wolf F, Phillips AN, Harris R, et al.
Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected
patients: a collaborative analysis of 18 HIV cohort studies. Lancet.
2009;373(9672):1352–63.
15. Severe P, Juste MA, Ambroise A, Eliacin L, Marchand C, Apollon S, et al.
Early versus standard antiretroviral therapy for HIV-infected adults in Haiti.
N Engl J Med. 2010;363(3):257–65.
16. Eholie SP, Vella S, Anglaret X. Commentary: Antiretroviral therapy initia‑
tion criteria in low resource settings—from ‘when to start’ to ‘when not to
start’. AIDS. 2014;28(Suppl 2):S101–4.
17. WHO. Guideline on when to start antiretroviral therapy and on preexposure prophylaxis for HIV. http://www.whoint/hiv/pub/guidelines/
earlyrelease-arv/en/.
18. EACS. Guidelines, Version 8.0. http://www.eacsocietyorg/files/
guidelines_8_0-english_webpdf.
19. DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents.
Guidelines for the use of antiretroviral agents in HIV-1-infected adults and
adolescents. Department of Health and Human Services. https://www.
aidsinfonihgov/contentfiles/lvguidelines/adultandadolescentglpdf.
20. International Antiviral Society-USA Panel. Antiretroviral Treatment of
Adult HIV Infection. https://www.iasusaorg/content/antiretroviral-treat‑
ment-adult-hiv-infection-0 (2015).
21. Insight START Study Group. Initiation of antiretroviral therapy in early
asymptomatic HIV infection. N Engl J Med. 2015;373(9):795–807.
22. ANRS Temprano 12136 Study Group. A trial of early antiretro‑
virals and isoniazid preventive therapy in Africa. N Engl J Med.
2015;373(9):808–22.
23. Grinsztejn B, Hosseinipour MC, Ribaudo HJ, Swindells S, Eron J, Chen YQ,
et al. Effects of early versus delayed initiation of antiretroviral treatment
on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN
052 randomised controlled trial. Lancet Infect Dis. 2014;14(4):281–90.
24. Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumar‑
asamy N, et al. Prevention of HIV-1 infection with early antiretroviral
therapy. N Engl J Med. 2011;365(6):493–505.
25. UNAIDS. The gap report. http://www.unaidsorg/sites/default/files/
media_asset/UNAIDS_Gap_report_enpdf.
26. Siedner M, Ng C, Bassett I, Katz I, Bangsberg D, Tsai A. Trends in CD4 count
at presentation to care and treatment initiation in sub-Saharan Africa,
2002–2013: a meta-analysis. Clin Infect Dis. 2015;60(7):1120–7.
Eholié et al. AIDS Res Ther (2016) 13:27
27. WHO. Consolidated guidelines on HIV testing services. http://www.
whoint/hiv/pub/guidelines/hiv-testing-services/en/.
28. Abdool Karim SS. Overcoming impediments to global implementation of
early antiretroviral therapy. N Engl J Med. 2015;373(9):875–6.
29. Vella S. End of AIDS on the horizon, but innovation needed to end HIV.
Lancet HIV. 2015;2(3):e74–5.
30. Flexner C, Plumley B. Brown Ripin DH. Treatment optimization: an outline
for future success. Curr Opin HIV AIDS. 2013;8(6):523–7.
31. Hatano H, Yukl SA, Ferre AL, Graf EH, Somsouk M, Sinclair E, et al. Prospec‑
tive antiretroviral treatment of asymptomatic, HIV-1 infected controllers.
PLoS Pathog. 2013;9(10):e1003691.
Page 9 of 9
32. UNAIDS. 90-90-90—An ambitious treatment target to help
end the AIDS epidemic. http://www.unaidsorg/en/resources/
documents/2014/90-90-90.
33. Granich R, Gupta S, Suthar AB, Smyth C, Hoos D, Vitoria M, et al. Antiret‑
roviral therapy in prevention of HIV and TB: update on current research
efforts. Curr HIV Res. 2011;9(6):446–69.
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